Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease

Margaret P Rayman

Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford,

GU2 7XH, UK

Margaret Rayman, Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University

of Surrey, Guildford, GU2 7XH Telephone: +44 (0)1483 686447. Fax: +44 (0)1483 686401 Email:

m.rayman@surrey.ac.uk

There are no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial or not-for-profit

sectors.

Key words: autoimmune thyroid disease; autoimmune thyroiditis; nutrition; iodine; iron; selenium

ABSTRACT

Hashimoto’s Thyroiditis (HT) and Graves’ Disease (GD) are examples of autoimmune thyroid disease (AITD),

the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses

thyroid-hormone production, and antibodies to the receptor for the thyroid-stimulating hormone (TSHR),

are characteristic of HT and GD, respectively. It is currently accepted that genetic susceptibility,

environmental factors, including nutritional factors, and immune disorders contribute to the development

of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and

treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to

provide a narrative review. Iodine: Chronic exposure to excess iodine intake induces autoimmune

thyroiditis, partly because highly-iodinated thyroglobulin is more immunogenic. Recent introduction of

universal salt iodisation can have a similar, though transient, effect. Iron: Iron deficiency impairs thyroid

metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are

frequently iron-deficient since autoimmune gastritis, which reduces iron absorption, and coeliac disease

which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of

hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/L

ameliorated symptoms. Selenium: Selenoproteins are essential to thyroid action. In particular, the

glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of

thyroglobulin to form thyroid hormones. There is evidence from observational studies and randomised

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controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration,

hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to

thyroid health.

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INTRODUCTION

The thyroid gland is the organ most commonly affected by autoimmune disease(1). Lymphocytic infiltration

of the thyroid is a frequent post-mortem finding in some 40% of white females and 20% of white males in

the US, with similar percentages of British white males and females being affected(2). In black Americans

and Japanese, the occurrence of lymphocytic thyroid infiltration was less than half that in Caucasians(2).

Autoimmune thyroid disease was probably first described in 1912 when a Japanese physician, Hakaru

Hashimoto, reported a condition where the thyroid was infiltrated by lymphocytes resulting in the

production of anti-thyroid antibodies(3).

Autoimmune thyroid disease (AITD), also known as autoimmune thyroiditis, has a multifactorial aetiology

involving both genetic, environmental and nutritional factors(4). It includes a spectrum of thyroid conditions

ranging from hypothyroidism, most notably Hashimoto’s Thyroiditis at one end, to hyperthyroidism, most

commonly Graves’ disease (GD) at the other end(4). In Hashimoto’s thyroiditis, the thyroid gland is gradually

destroyed resulting in reduced production of thyroid hormones and triggering symptoms that include

fatigue, weight gain, constipation, increased sensitivity to cold, dry skin, depression, muscle aches and

reduced exercise tolerance(5). Hashimoto’s thyroiditis affects more than 15% of females over 60 years and

2% of males(6). It is defined by the presence of antibodies (Ab) to thyroid peroxidase (TPO), the thyroid

enzyme that oxidises iodide to iodine for thyroid hormone synthesis(4). In addition, antibodies (Tg-Ab) to

thyroglobulin (Tg), the protein on which thyroid hormones are synthesised by iodination of its tyrosine

residues, are frequently present(4). In Graves’ disease, the major autoantigen (TSHR-Ab) is to the receptor

for the thyroid-stimulating hormone (TSH), which causes overproduction of thyroid hormones, resulting in

symptoms such as irritability, rapid heartbeat, weight loss, poor tolerance of heat and bulging eyes (Graves’

orbitopathy)(4; 7; 8).

Nutritional factors that affect thyroid function include the micronutrients iodine, iron and selenium (9); these

will be discussed below. Though vitamin D has been postulated to affect thyroid function, the evidence is

insufficient(9) to include it in the current review.

PubMed and the Cochrane Library were searched for publications up to March 2018 using the search terms

“autoimmune thyroiditis” OR “autoimmune thyroid disease” in combination with “iodine”, “selenium”,

“iron” and “nutrition OR diet”. Articles were filtered by relevance of title, abstract and finally the full text.

Relevant conclusions or results were extracted from each article to provide a narrative review.

Iodine

Role of iodine in the thyroid

Iodine is a key constituent of the thyroid hormones, thyroxine (T4, pro-hormone) and tri-iodothyronine (T3,

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active hormone), as shown in Figure 1, which also depicts the key players in thyroid hormone synthesis that

takes place in the thyroid follicular cells(10).

Iodine and Autoimmune Thyroid Disease (AITD)

The association between iodine intake and the presence of circulating thyroid antibodies is complex with

iodine intake both below and above the recommended level being associated with an increase in circulating

antibodies(11). Circulating TPO-Ab and Tg-Ab are common both in populations with a stable high iodine

intake and those with mild and moderate iodine deficiency(12). Deficient iodine intake can lead to nodular

goitre in which thyroid antigens are released from the abnormal gland, resulting in the presence of thyroid

antibodies in the circulation(13). However, excess iodine intake or a rise in intake following iodine

fortification of an iodine-deficient population also gives an increased risk of thyroid autoimmunity, as

attested by studies in many countries(14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24). In China, for instance, three years after the

introduction of salt iodisation in 1996, the prevalence of AITD was 0.5% in an area of mildly deficient iodine

intake, 1.7% in an area of more-than-adequate iodine intake and 2.8% in an area of excessive iodine

intake(14). In Denmark, formerly a region of mild-to-moderate iodine deficiency [median urinary iodine

concentration (UIC) 61 µg/L], five years after the mandatory iodine fortification of salt, iodine status had

significantly improved (median UIC 101 µg/L), but the prevalence of thyroid antibodies had risen, i.e., TPO-

Ab > 30 U/ml increased from 14% to 24% and Tg-Ab > 20 U/ml increased from 14% to 20%(18). However,

despite the short-term adverse effects on thyroid autoimmunity, raising iodine intake from a deficient to an

optimal intake-level ultimately results in decreased prevalence of AITD; Denmark is an example of this (11; 25).

Potential mechanisms by which high or increased iodine intake raises AITD risk

The increase in circulating antibodies associated with iodine fortification is probably due to a number of

factors including the strong immunogenicity of highly iodinated thyroglobulin (Tg) which may trigger an

immune reaction against the thyroid gland(25; 26). An additional factor may be that excess iodine intake

increases the expression of the intercellular adhesion molecule 1 (ICAM-1), on the thyrocyte causing

accelerated mononuclear cell infiltration and inflammation(26). This has been demonstrated in the

NOD.H2h4 mouse model of autoimmune thyroiditis where iodide treatment enhanced the transcription of

ICAM-1 triggered by reactive oxygen species (ROS) and, in particular, by hydrogen peroxide (H2O2)

generated in the thyrocyte for the organification of iodine (26; 27). Other likely effects of high iodine intake in

susceptible individuals are an increased production of thyroid-infiltrating T helper 17 (Th17) cells, inhibition

of T regulatory (TREG) cell development and an abnormal expression of tumour necrosis factor-related

apoptosis-inducing ligand (TRAIL) in thyrocytes, resulting in apoptosis and tissue destruction (28).

Iodine-intake recommendations to reduce AITD risk

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With regard to autoimmune thyroiditis, as can be seen from the above section, there is more evidence for

an association with iodine excess than with deficiency, especially in genetically susceptible individuals (14; 28;

29). It is therefore important to ensure, as far as possible, that iodine intake falls within the recommended

levels(11) [see Table 1(30; 31; 32)]{Institute of Medicine, 2011 #82}. On a population basis, this would be

represented by a median UIC in adults of 100-200 µg/l. Authorities introducing iodine fortification of the

food supply in a country (e.g. universal salt iodisation) need to ensure that such fortification is introduced

very cautiously; Denmark provides an excellent example of how this can be done (33). Individuals living in a

country that does not have an iodine-fortified food supply who avoid the main food sources of iodine, i.e.

milk and dairy products, seafood, most notably haddock, cod, crab, large/Dublin-bay prawns (often called

scampi) and eggs, and do not use iodised salt, should be advised to take a daily supplement containing 140-

150 µg iodine for thyroid protection, particularly if planning pregnancy (34; 35; 36). Though high in iodine, intake

of brown seaweed (e.g. kelp/kombu), or brown-seaweed supplements should be avoided in case of

excessive intake(37).

Iron

Role of iron in the thyroid

A haem-dependent enzyme, TPO, that has iron at its active centre, is required for thyroid hormone

synthesis, as illustrated in Figure 1(38; 39). TPO becomes active at the apical surface of thyrocytes only after it

binds a prosthetic haem group(40), hence an adequate iron status is required for the synthesis of thyroid

hormones.

Co-morbidity of AITD and other autoimmune conditions

It is not always appreciated that iron deficiency is common in people with AITD owing to the frequent co-

morbidity of other autoimmune conditions such as coeliac disease(41; 42; 43) and autoimmune gastritis(44; 45; 46; 47)

that often cause iron deficiency. Patients with subclinical hypothyroidism or Hashimoto’s Thyroiditis

frequently have lower serum iron concentration and a higher prevalence of iron deficiency than do healthy

controls(48; 49). A symbiotic relationship exists between active thyroid hormone concentration and the

formation of red blood cells; T3 is needed to stimulate the proliferation of red-blood-cell precursors, both

directly and by enhancing the production of erythropoietin (EPO)(50).

Dependence of thyroid function on iron status

Iron deficiency reduces thyroid hormone production by decreasing the activity of TPO (38; 39; 40). Evidence of

the dependency of thyroid function on iron status comes from both animal and human studies. In rodents,

iron deficiency, with or without anaemia, decreased serum T4 and T3 concentrations, lowered 5 ꞌ-

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deiodinase (DIO) activity, and reduced the ability to thermoregulate in response to a cold environment (39; 51;

52; 53). In US women with mild iron-deficiency anaemia (haemoglobin, Hb, 110 g/L), serum T3 and T4 were

significantly lower than in iron-sufficient controls(54). Furthermore, iron deficiency predicts poor maternal

thyroid status in pregnancy; in a study on 365 Swiss pregnant women in the second and third trimesters

with borderline iodine deficiency (median urinary iodine concentration 139 µg/L), concentrations of TSH,

total T4 and urinary iodine were measured. Body iron stores, calculated from blood Hb concentration,

mean corpuscular volume, serum ferritin, and transferrin receptor were highly significant predictors of TSH

and total T4 (P<0.0001)(55). We also know that iron deficiency (ID) is associated with hypothyroxinaemia;

serum free T4 concentrations were significantly lower in both 3,340 pregnant and 1,052 non-pregnant

Chinese women with iron deficiency than in iron-adequate women(56).

Effect of low iron stores on efficacy of treatment for hypothyroidism

It is important to recognise that low iron stores may contribute to symptom persistence in patients treated

for hypothyroidism in 5–10% of whom symptoms remain despite being treated with levothyroxine (L-T4) (57).

An example is afforded by a small study in 25 Finnish women with persistent symptoms of hypothyroidism,

despite appropriate L-T4 therapy, who became symptom-free when treated with oral iron supplements for

6-12 months(58). None of the women had anaemia or red-cell indices outside the reference range though all

had serum ferritin < 60 µg/L. Restoration of serum ferritin above 100 µg/L ameliorated the symptoms in

two-thirds of the women. At least 30 – 50% of hypothyroid patients with persisting symptoms despite

adequate L-T4 therapy may, in fact, have covert iron deficiency(58).

Supplementation with thyroid hormone can improve iron status

An interesting fact is that supplementation with thyroid hormone in patients with subclinical

hypothyroidism improves iron status. Early experiments in hypothyroid rats showed diminished

gastrointestinal iron absorption that was restored to normal on supplementation with T3 (59). In iron-

deficient women with subclinical hypothyroidism treated for one year with T4, the frequency of anaemia

decreased (p = 0.001) while ferritin, iron and Hb levels slightly increased (p > 0.05) (49). In untreated women,

further decrease in ferritin level and increase in anaemia occurred(49). In two randomised controlled trials in

patients with coexisting iron-deficiency anaemia and sub-clinical hypothyroidism, treatment with iron and

L-T4 together was considerably more effective in improving iron status than was treatment with iron

alone(60; 61).

Recommendations for iron intake in thyroid patients

Patients with AITD or hypothyroidism should be routinely screened for iron deficiency. If either iron

deficiency or serum ferritin below 70 µg/L is found(58), coeliac disease or autoimmune gastritis may be the

cause and should be treated. Medication that reduces the acidity of stomach contents (e.g. proton pump

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inhibitors) may also cause reduced iron absorption(62). If iron-deficiency anaemia is present, haematological

testing can be used to rule out the anaemia of chronic disease as the cause. In the absence of the latter,

supplementation should be begun to restore iron sufficiency and prevent its deleterious effects on thyroid

function(63; 64).

Once iron sufficiency is restored, assuming there is no underlying clinical cause of deficiency, patients need

to be told how to optimise their dietary iron intake. Foods with relatively high iron concentration include

meat, fish, cereals, beans, nuts, egg yolks, dark green vegetables, potatoes and fortified foods (65). However,

iron is inefficiently absorbed, its bioavailability from different foods being markedly variable; bioavailability

has been estimated to be in the range of 14-18% for mixed diets and 5-12% for vegetarian diets in

individuals with no iron stores(66). Absorption depends on a number of dietary and host-related factors;

haem iron (from animal tissues) is considerably better absorbed than non-haem iron, though the latter

constitutes 90 % of the iron in a mixed diet. Dietary factors that reduce non-haem iron absorption include

phytate, polyphenols and calcium, while those that increase it include ascorbic acid and muscle tissue (66).

Following dietary advice, iron status should be checked regularly.

Selenium

Role of selenium in the thyroid: selenoproteins

The thyroid contains the highest concentration of selenium in the human body and is able to retain it even

under conditions of severe deficiency(67). A number of selenoproteins are expressed in thyrocytes(68), those

named below being particularly important to thyroid function.

The deiodinases (DIO): DIO1 and DIO2 can activate T4 by transforming it into T3 by removal of the 5ʹ-iodine,

while DIO1 and DIO3 can prevent T4 from being activated by converting it to the inactive reverse T3 (69)

(Figure 2). DIO3 can also inactivate T3 by 5-deiodination to diiodothyronine (T2). DIO2 is largely responsible

for local conversion of T4 to T3 in extrathyroidal target tissues(70). A major role of DIO3 is to protect

sensitive cells, such as foetal tissue, the placenta and central nervous system, from excessive

concentrations of the active hormone, T3(70; 71).

The glutathione peroxidases (GPX): Extracellular GPX3 is the only actively secreted GPX isozyme that is

abundantly expressed in the thyroid gland(72). It is secreted at the apical side of the thyrocyte membrane

where it converts excess H2O2 that has not been used by TPO for the iodination of tyrosyl residues of

thyroglobulin or for iodotyrosine coupling, into harmless water(73).

Selenoprotein S (SELENOS): SELENOS is involved in the control of the inflammatory response in the

endoplasmic reticulum (ER) by retrotranslocation of misfolded proteins from the ER lumen to the cytosol (74).

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In a Portuguese study, the SELENOS−105G/A promoter polymorphism (rs28665122) was strongly associated

with circulating levels of cytokines such as IL-1β, IL-6, and TNF-α, known to be involved in the pathogenesis

of Hashimoto’s Thyroiditis(75; 76). Those with the SELENOS GA and AA genotypes were significantly more

likely to have Hashimoto’s Thyroiditis: OR (95% CI) for Hashimoto’s Thyroiditis was 2.22 (1.67–2.95) and in

male A-allele carriers, 3.94 (1.43–10.84).

Effect of selenium status on thyroid disease

Selenium deficiency has been associated with a number of adverse thyroid conditions, including

hypothyroidism, subclinical hypothyroidism, enlarged thyroid(77; 78; 79; 80), thyroid cancer(68; 80; 81; 82), and AITD,

including Hashimoto’s Thyroiditis(78; 80) and Graves’ Disease(80; 83).

A study of thyroid disease prevalence in more than 6000 people from two counties of Shaanxi Province,

China, of very different selenium status – adequate and low – showed the protective effect of selenium

adequacy(78). Median (IQR) serum selenium concentration differed almost two-fold [103.6 (79.7, 135.9) vs.

57.4 (39.4, 82.1) μg/L; P=0.001] between the two counties though iodine status was comparable (84). After

adjustment for potential confounders, the prevalence of pathological thyroid conditions was significantly

lower in the adequate-selenium than in the low-selenium county (18.0% vs. 30.5%; P<0.001). Higher serum

selenium was associated with significantly lower odds [OR (95% CI)] of autoimmune thyroiditis [0.47 (0.35,

0.65)], hypothyroidism [0.75 (0.63, 0.90)], subclinical hypothyroidism [0.68 (0.58, 0.93)], and enlarged

thyroid [0.75 (0.59, 0.97)](78). The iodine intake was “more-than-adequate”(78; 85; 86) in both counties which

may have accounted to some extent for the high prevalence of thyroid disease (87; 88).

Selenium status has been found to be significantly lower in patients with Graves’ Disease than in normal

controls in Danish(89) and Chinese studies(90). In the latter, serum selenium was negatively correlated with

serum titre of TPO-Ab (r = −0.161, p = 0.021), and Tg-Ab (r = −0.237, p = 0.001) (90). In a prospective, case-

control study in an Australian population, mean serum selenium decreased in parallel with increasing

severity of Graves' orbitopathy: 94.0 ± 15.8 μg/L in Graves’ Disease, 86.9 ± 15.0 μg/L in moderate-to-severe

Graves' orbitopathy and 86.1 ± 13.4 μg/L in sight-threatening Graves' orbitopathy (P = 0·003)(91). However,

these data may simply reflect the presence of inflammation in Graves’ Disease and more especially in

Graves’ orbitopathy; the expression of selenoproteins including plasma SELENOP is reduced by

inflammatory cytokines resulting in a fall in plasma selenium(92; 93).

Randomised controlled trials of selenium in thyroid disease

Several trials of selenium supplementation have been carried out in AITD/Hashimoto’s thyroiditis and mild

Graves' orbitopathy.

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In a large, multicentre, randomised, controlled trial (RCT) with selenium, patients with mild Graves’

orbitopathy significantly improved on treatment with 100 g selenium twice/day (as sodium selenite) for

six months(94). Patients on selenium treatment had improved quality of life (P<0.001), less eye involvement

(P=0.01) and slower disease progression (P=0.01). The benefit persisted at the 12-month follow-up. A

protocol for an RCT of selenium in patients with Graves' hyperthyroidism (the GRASS trial) was published in

2013(95). The primary outcome is the proportion of participants with anti-thyroid drug treatment failure at

the end of the intervention period (24-30 months). Secondary outcomes include thyroid-specific quality of

life and eye symptoms during the first year after randomisation(95). The results of the trial have not yet been

reported.

There have been a number of systematic reviews/meta-analyses of controlled trials of selenium treatment

in patients with AITD/Hashimoto’s thyroiditis(71; 96; 97; 98). The most recent is a 2016 meta-analysis of 16 trials

that found that selenium supplementation reduced serum TPO-Ab levels after 3, 6 and 12 months in a

population with chronic autoimmune thyroiditis treated with L-T4(96). However, in an untreated

autoimmune thyroiditis population, the effect was significant only after three months(96). Some of these

studies also saw a reduction in Tg-Ab titre at 12 months, an improvement in thyroid echogenicity, and an

increase in subjective well-being. Unfortunately, the methodology of many of the studies was flawed –

underpowered, not double-blinded, not placebo-controlled, and disparities in iodine intake were not

considered(96; 97; 99). The beneficial effect in some studies and not in others cannot easily be explained on the

basis of baseline selenium status, stage of disease, baseline TPO-Ab titres, form or dose of selenium

used(100). Later studies not included in these meta-analyses have been too small to contribute meaningful

data(101; 102). Well designed, properly powered, RCTs of selenium in the treatment of AITD/Hashimoto’s

thyroiditis are therefore still needed before we can confidently recommend selenium supplementation in

these patients. The protocol for a new, high-quality, trial of selenium supplementation (Catalyst Trial) in

patients with chronic autoimmune thyroiditis has been published(103). We await the results with interest.

The presence of thyroid autoantibodies is relatively high in women of childbearing age (104). One notable RCT

has been carried out in pregnant women positive for TPO-Abs. Up to 50% of such women develop

postpartum thyroiditis of whom 20-40% subsequently become hypothyroid(105). In an Italian study, 151 TPO-

Ab-positive women were randomly assigned to supplementation with 200 g selenium/d (as

selenomethionine) or placebo during pregnancy and the post-partum period (106) (56). TPO-Abs fell

significantly during gestation in both groups but the reduction was significantly greater in the selenium-

supplemented group (P=0.01) and remained so in the postpartum period (P=0.01) (see Figure 3). Compared

to women on placebo, those on selenium had a significantly lower incidence of post-partum thyroid disease

(28.6% vs 48.6%; P<0.01) and permanent hypothyroidism (11.7% vs 20.3%; P<0.01). In contrast to women

on placebo, ultra-sound echogenicity did not fall in those supplemented with selenium. At the end of the

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postpartum period, grade 2-3 thyroiditis had developed in 44.3% of women on placebo but only in 27.3% of

women on selenium (P<0.01)(106).

The only other RCT that investigated the effect of selenium supplementation on autoimmune thyroid

disease in pregnancy found no difference in the magnitude of TPO-Ab decrease between selenium and

placebo groups(107). However the median baseline TPO-Ab concentrations in the women were much lower

than in the above study, the selenium dose was less than one third as high (60 μg/d) and the trial was not

adequately powered(107). Clearly there is a need for a further, high-quality, adequately powered RCT in the

TPO-Ab-positive pregnant population to see if the results of the Italian study can be replicated (108).

Is selenium intake adequate to reduce the risk of thyroid disease?

Selenium intake differs vastly from one part of the world to another owing to differences in the selenium

content of the soil on which crops and fodder are grown, selenium speciation, soil pH and organic-matter

content(109). Intake ranges from deficient (7 g/d) to toxic (4990 g/d) as shown in Figure 4(110; 111). A vertical

band in Figure 4 shows the level of intake believed to be needed to optimise the activity of GPX3 (112), the

main selenoenzyme that removes excess H2O2 from the thyroid. It is clear that the mean intake in many

countries, notably those in Europe, does not achieve that level.

Recommendations for selenium intake

Though we lack evidence that selenium supplementation results in clinical improvement in autoimmune

thyroiditis (other than in mild Graves’ orbitopathy), it still makes sense to ensure that selenium intake is

adequate, given the roles played by selenoproteins in human health (110) and particularly in the thyroid(72; 113).

Regions of deficient, more-than-adequate or high iodine intake may have more need for selenium owing to

the capacity of selenoproteins to protect the thyroid from excessive H2O2(113) and from inflammation(75) (see

above). Hence, in such locations, clinicians need to ensure that selenium intake/status is adequate. Women

are at greater risk of thyroid disorders and may thus have a higher requirement for additional selenium,

particularly in pregnancy. Geographical location will give a good indication of selenium adequacy or

otherwise (see Figure 4).

It is also important to enquire into the dietary habits of a given patient and see if he/she eats foods that

supply selenium(114). Though Brazil nuts are the richest selenium food source they cannot be recommended

as a main source as the content is very variable, ranging from 0.03 to 512 mg/kg fresh weight, and they are

high in barium, which can be toxic(115). Otherwise, organ meats and seafoods are the best sources, followed

by muscle meats, cereals and grains, though the selenium content of the latter varies widely with location,

being towards or at the bottom of the range in the UK and Europe but at the top in North America, most

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notably in Canada (see Figure 5)(114; 115). In China, selenium-enriched tea is an option(78). Given the sources

described, vegans and vegetarians in the West are particularly at risk of inadequate selenium intake.

If a patient’s diet in a country of low-to-moderate selenium intake contains few, or no, selenium-rich

sources, low-dose selenium supplementation can be advised though no more than 50-100 µg selenium/day

is advisable. Multi-vitamin/mineral tablets may contain 50 µg selenium, a daily amount that will generally

be adequate, particularly for women. A dose of 100 µg selenium/day (as selenium-yeast) given to someone

in the UK will raise plasma selenium to around 140 µg/L which is more than enough to optimise the

synthesis of all the selenoproteins(116). Either selenium-yeast (which behaves in the body like wheat-

selenium) or sodium selenite which the body can readily use for selenoprotein synthesis without increasing

the build-up of selenium, will do(115).

Clinicians should be aware that even if a hypothyroid patient is being treated with levothyroxine, a number

of studies have found that giving selenium as well as levothyroxine resulted in a greater reduction in TPO-

Abs, inflammatory cytokines and C-reactive protein(117; 118).

Though selenium is essential, excessive intake is toxic; supplements of selenium of 200 µg/day (as selenium

yeast or selenomethionine), generally considered to be safe, have been associated with toxic effects

(alopecia, dermatitis, squamous cell carcinoma, type-2 diabetes mellitus, high-grade prostate cancer) in

North Americans(119; 120; 121). If selenium concentration reaches or exceeds 122 µg/L in plasma, as in the top

tertile of the Nutritional Prevention of Cancer trial(122) or is already 137 µg/L in serum, as in SELECT(119),

supplementation should be avoided(119; 123; 124; 125). Furthermore, mortality was found to be increased in a

European population of relatively low selenium status (plasma selenium 89 µg/L) on long-term

supplementation with 300 µg/d (as selenium-yeast)(126). As for many nutrients, there is a U-shaped

relationship between selenium status and risk of a number of adverse conditions(110). The aim should

therefore be to have an intake sufficient to reduce the risk of thyroid disease without risking toxicity (114).

Conclusion

As explained in detail above, appropriate status of iodine, iron and selenium is crucial to thyroid health.

Nutritional status of these micronutrients is frequently inadequate: iodine status is often low in countries

without iodine fortification of the food supply; selenium status is generally fairly poor in Europe and many

parts of China; iron status is frequently low in women of childbearing age, particularly towards the end of

pregnancy. Clinicians need to be aware of these dietary risk factors and to treat thyroid patients

accordingly.

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Acknowledgement: I thank Shiqian Hu, Department of Endocrinology, First Affiliated Hospital of Xi’an

Jiaotong University, Xi’an, Shaanxi, China, who worked with me on investigating the effect of

micronutrients on Hashimoto’s thyroiditis when on a placement at the University of Surrrey.

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Table 1. Iodine intake requirements by life stage according to various authorities

Age EFSA AI

(µg/d)(30)

USA RDA

(µg/d)(31)

ICCIDD/UNICEF/WHO RNI (µg/d)

(32)

0-6 mth - 110 (AI) 90

7-12 mth 70 130 (AI) 90

1-6 yr 90 90 90

7-10 yr 90 90-120 120

11-14 yr 120 120-150 120-150

15-17 yr 130 - -

15-50 yr - 150 150

≥ 18 yr 150 - -

Pregnancy 200 220 250

Lactation 200 290 250

Abbreviations: AI, Adequate Intake; RDA, Recommended Dietary Allowance; RNI Recommended Nutrient

Intake.

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Figure legends

Figure 1. Synthesis of the thyroid hormones in the thyroid follicle (modified from Häggström 2014(10)).

Thyroglobulin is synthesized in the rough endoplasmic reticulum and follows the secretory pathway to

enter the colloid in the lumen of the thyroid follicle by exocytosis. Meanwhile, a sodium-iodide (Na/I)

symporter pumps iodide (I-) actively into the cell, which previously has crossed the endothelium by largely

unknown mechanisms. This iodide enters the follicular lumen from the cytoplasm by the

transporter pendrin, in a purportedly passive manner. In the colloid, iodide (I-) is oxidized to iodine (I0) by

hydrogen peroxide (H2O2) with the help of an enzyme called thyroid peroxidase (TPO). Iodine (I0) is very

reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain (in total containing

approximately 120 tyrosyl residues). In conjugation, adjacent tyrosyl residues are paired together, again

under the influence of TPO and H2O2. The entire complex re-enters the follicular cell by endocytosis.

Proteolysis by various proteases liberates thyroxine and triiodothyronine molecules, which enter the blood

via a monocarboxylate transporter (MCT).

Figure 2. Action of the iodothyronine deiodinases, DIO1, DIO2 and DIO3, to produce the active and inactive

forms of thyroid hormone

Figure 3. Selenium protects against post-partum autoimmune thyroid disease [adapted from Negro et al.

2007(106) with permission]

Figure 4. Mean selenium intake levels (g/d) in different countries and the range of selenium intake (55-75

g/d) believed to be required for optimal activity of plasma glutathione peroxidase (GPX3) [adapted from

Rayman 2005(111)]

Figure 5. Typical selenium content of food sources, adapted from WHO. Selenium. A report of the

International Programme on Chemical Safety. Environmental Health Criteria number 58. Geneva: WHO,

1987 (reproduced from Rayman 2012(110))

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